Parsing molecular and behavioral effects of cocaine in mitogen- and stress-activated protein kinase-1-deficient mice
Parsing molecular and behavioral effects of cocaine in mitogen- and stress-activated protein kinase-1-deficient mice
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DOI：
10.1523/jneurosci.1711-05.2005
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发表时间：
2005-12-07
影响因子：
5.3
通讯作者：
Caboche, J
中科院分区：
文献类型：
--
作者：
Brami-Cherrier, K;Valjent, E;Caboche, J
虽然滥用药物诱导的持续性行为改变需要基因转录的调节，但涉及的确切细胞内信号通路仍然主要未知。细胞外信号调节激酶(ERK)是纹状体即刻早期基因表达的关键，对可卡因和Delta 9-四氢大麻酚的反应以及这些药物的奖励特性至关重要。在这里，我们表明，在小鼠中，一次注射可卡因(10 mg/kg)可以激活背侧纹状体和伏隔核中的丝裂原和应激激活蛋白激酶1(MSK1)。可卡因诱导的MSK1苏氨酸581和cAMP反应元件结合蛋白(CREB)丝氨酸133(Ser(133))的磷酸化可被阻止ERK激活的药物SL327阻断。可卡因使组蛋白H4赖氨酸5乙酰化和组蛋白H3Ser(10)磷酸化增加，表明体内存在药物诱导的染色质重塑。在MSK1基因敲除(KO)小鼠中，可卡因(10 mg/kg)对CREB和H3的磷酸化反应被阻断，c-Fos和强啡肽的诱导被阻止，而Egr-1(早期生长反应-1)/Zif268/Krox24的诱导没有改变。MSK1-KO小鼠没有明显的神经缺陷，但对可卡因的反应表现出不同的行为表型。可卡因和多巴胺D-1或D-2激动剂的急性效应没有改变。在条件性位置偏爱范式中，对低剂量但不是高剂量可卡因的敏感度增加，而对重复注射可卡因的运动敏感度显著降低。我们的结果表明，MSK1是ERK下游的一种主要的纹状体激酶，负责CREB和H3的磷酸化，是诱导c-Fos和强啡肽以及运动敏化所必需的。
Although the induction of persistent behavioral alterations by drugs of abuse requires the regulation of gene transcription, the precise intracellular signaling pathways that are involved remain mainly unknown. Extracellular signal-regulated kinase (ERK) is critical for the expression of immediate-early genes in the striatum in response to cocaine and Delta 9-tetrahydrocannabinol and for the rewarding properties of these drugs. Here we show that in mice a single injection of cocaine (10 mg/kg) activates mitogen- and stress-activated protein kinase 1 (MSK1) in dorsal striatum and nucleus accumbens. Cocaine-induced phosphorylation of MSK1 threonine 581 and cAMP response element-binding protein (CREB) serine 133 (Ser(133)) were blocked by SL327, a drug that prevents ERK activation. Cocaine increased the acetylation of histone H4 lysine 5 and phosphorylation of histone H3 Ser(10), demonstrating the existence of drug-induced chromatin remodeling in vivo. In MSK1 knock-out (KO) mice CREB and H3 phosphorylation in response to cocaine (10 mg/kg) were blocked, and induction of c-Fos and dynorphin was prevented, whereas the induction of Egr-1 (early growth response-1)/zif268/Krox24 was unaltered. MSK1-KO mice had no obvious neurological defect but displayed a contrasted behavioral phenotype in response to cocaine. Acute effects of cocaine and dopamine D-1 or D-2 agonists were unaltered. Sensitivity to low doses, but not high doses, of cocaine was increased in the conditioned place preference paradigm, whereas locomotor sensitization to repeated injections of cocaine was decreased markedly. Our results show that MSK1 is a major striatal kinase, downstream from ERK, responsible for the phosphorylation of CREB and H3 and is required specifically for the induction of c-Fos and dynorphin as well as for locomotor sensitization.